Congenital heart disease (CHD) is the most common birth defect affecting up to 2% of live births and is associated with serious complications and life-long management. Genome scanning is a developing standard of care for CHD patients, which identifies genetic etiology in only about 10-20% of cases. For these patients, discovery of the pathogenic gene offers targeted therapies for improved outcomes. The genetic cause for the remaining 80-90% of cases remain undefined, leaving patients deprived of optimized personal treatments. By taking genomic information from CHD patients and modeling genetic aberrations in Drosophila, novel CHD candidates will be identified and their role in cardiac development and pathogenesis can be better understood, which will provide much needed genetic information to drive treatment for CHD patients. For example, the gene Nascent polypeptide Associated Complex-? (NAC?) was identified from a screen utilizing patient information. Preliminary data suggest that NAC? is involved in heart remodeling during fly metamorphosis. Knocking down NAC? levels results in an unremarkable cardiac phenotype in larvae however, intriguingly, following metamorphosis, adult flies lack a heart. The functional role for NAC? will be explored during embryonic and pupal stages, by evaluating its interactions with its heterodimeric partner (bicaudal) and developmental genes known as hox genes (abd-A and abd-B) in setting the spatial boundaries for apoptotic events necessary for remodeling of the heart. Because of the high similarity in developmental processes between Drosophila and vertebrates, these findings will translate and influence studies in mammals. In order to identify novel CHD genes, we will screen in Drosophila, genes that are found within Copy Number Variants (CNV) regions of CHD patients. CNVs are deleted/duplicated genomic regions between 1KB-5MB that are present at higher rates in CHD patients and likely contain pathogenic genes. By misexpressing these candidate CHD genes in flies, pathogenic genes will be identified by assessing their impact on cardiac function and development. The candidate genes will also be misexpressed in commercially available human iPS-derived cardiomyocytes, to assess for changes in Ca2+ handling and cell division/differentiation, which could provide mechanistic insight and narrow down a conserved function. Future work can test the functional interactions and relationships between candidate genes and known developmental genes, which will help grow and refine the established genetic network driving development. Establishing the developmental roles of candidate CHD genes will allow for their categorization that should improve CHD diagnosis. Furthermore, an enhanced understanding of development may uncover novel therapeutic targets leading to personalized treatment of CHD and other cardiac conditions.